PROJECT SUMMARY Circadian rhythms strongly influence cell cycle and proliferation, and play a fundamental role in the maintenance of gastrointestinal physiology. Various gastrointestinal functions show a daily rhythmicity including gastric acid secretion, motility and intestinal stem cell regeneration and function, thus suggesting that these rhythms are under circadian clock control. This recognition has led to the application of chronotherapy (i.e. finding the right target and timing for disease treatments) in the treatment of colorectal cancer, improving patient survival. Importantly, disruption of key components of the molecular oscillator that generates circadian rhythms, such as Per2 and Bmal1, promotes the development of gastrointestinal tumors, yet the molecular mechanisms that connect circadian rhythms and cell cycle, and the physiological significance of this coupling remain largely unknown. Intriguingly, circadian rhythms are dysregulated in most human cancers suggesting that cancer cells impair the circadian clock to achieve uncontrolled growth and proliferation. In the proposed project, we propose to: (1) elucidate the consequence of the coupling between the circadian clock and cell cycle by integrating computational simulations and experimental validations, and (2) determine whether circadian rhythms regulate cell proliferation and tumor development using mouse enteroids. Our results will lay a foundation for identifying potential targets and temporal regimens to treat cancer.